Injectable pharmaceutical composition comprising ursodesoxycholic acid or tauroursodesoxycholic acid, a strong base and tromethamol

ABSTRACT

Injectable aqueous composition comprising ursodeoxycholic acid or tauroursodeoxycholic acid, a strong base compatible with intravenous injection and trometamol.

The present invention relates to a novel pharmaceutical compositionbased on ursodeoxycholic acid, either as such or conjugated withtaurine.

In particular, the invention relates to an injectable formulation ofursodeoxycholic acid or tauroursodeoxycholic acid for intravenousadministration, especially by slow perfusion.

Ursodeoxycholic acid and tauroursodeoxycholic acid are drugs which arewidely used in therapy as litholytics and in the treatment of variouspathological conditions of the liver, such as hepatic cholestasis andprimary biliary cirrhosis. It has now been found that the action ofthese drugs is also particularly useful in the treatment of pathologicalconditions of the liver in patients for whom oral administration isimpossible or difficult.

No injectable pharmaceutical formulations based on ursodeoxycholic acidor tauroursodeoxycholic acid are currently available on the marketbecause their preparation presents problems due to the physicochemicalproperties of these active principles.

Ursodeoxycholic acid is a weak acid which is practically insoluble inwater; its solubility increases greatly in the presence of strong basessuch as sodium hydroxide and potassium hydroxide. However, aqueoussolutions consisting solely of ursodeoxycholic acid and a strong baseare not suitable for intravenous administration because even a smallvariation in the amount of strong base in the preparation leads to aconsequent variation in the pH of the injectable solution which is oftenincompatible with intravenous administration.

In contrast to ursodeoxycholic acid, tauroursodeoxycholic acid is astrong acid which is soluble in water, its pKa being about 1.4. Thisstrong acidity is incompatible with intravenous administration; in thiscase too, it is possible to resort to the addition of bases to thesolution, although the above-mentioned problems of pH variation stillremain unsolved.

Also, ursodeoxycholic and tauroursodeoxycholic acids are detergentcompounds and, for this reason, cause foaming when added to an aqueoussolution such as the solution for intravenous perfusion.

It has now been found that the addition of trometamol((trishydroxymethyl)aminomethane) to an aqueous solution containingursodeoxycholic acid or tauroursodeoxycholic acid and strong basesproduces stable, well-buffered solutions suitable for intravenousadministration.

It has moreover been observed that the addition of trometamolsurprisingly reduces foaming and the persistence of the foam which formsin the solution for intravenous perfusion following the addition of theabove preparation.

The present invention therefore relates to an injectable aqueouscomposition which comprises ursodeoxycholic acid or tauroursodeoxycholicacid, a strong base compatible with intravenous administration, andtrometamol.

According to the present invention, the water used is suitable forinjectable preparations.

The formulation according to the invention comprises an amount of activeprinciple--ursodeoxycholic acid or tauroursodeoxycholic acid--of between1 and 30% (w/v) and preferably of between 5 and 20% (w/v), for example10% (w/v).

The strong base compatible with intravenous administration is preferablysodium or potassium hydroxide; such bases are used in astoichiometrically equivalent amount relative to the acid employed.

The trometamol is added at a rate of 0.01-2% (w/v), preferably at a rateof about 0.1% (w/v).

The formulation according to the invention advantageously consists of anaqueous solution which comprises from 5 to 15% (w/v) of active principle(ursodeoxycholic acid or tauroursodeoxycholic acid), astoichiometrically equivalent amount of strong base (sodium or potassiumhydroxide) and from 0.05 to 0.2% (w/v) of trometamol, ursodeoxycholicacid being the preferred active principle.

The injectable aqueous formulation forming the subject of the presentinvention preferably contains about 10% (w/v) of ursodeoxycholic acid,about 1% (w/v) of sodium hydroxide and about 0.1% (w/v) of trometamol.

The formulation of the present invention is prepared by separatelymixing the different components with distilled water and subsequentlycombining the solutions/suspensions obtained. It is thereforeappropriate to filter the solution in order to remove any residues, andsterilize it.

Preferably, before sterilization, which is performed in an autoclave,the solution is subdivided into ampoules or single-dose bottles, thisoperation optionally being carried out under a nitrogen atmosphere, and,when it is used, it is diluted in the solution for intravenous perfusionin order to be administered by slow perfusion.

If it were desired to use multi-dose containers, it could be appropriateto add a bactericide to the composition.

A particularly advantageous solution for intravenous perfusion is the(conventional) isotonic solution (containing 0.9% of sodium chloride).

Isotonic solutions for intravenous perfusion which contain the abovecomposition are also a subject of the present invention.

More particularly, the invention further relates to a composition forintravenous perfusion which comprises isotonic solution, ursodeoxycholicacid or tauroursodeoxycholic acid, a strong base compatible withintravenous administration in a stoichiometrically equivalent amountrelative to the acid employed, and trometamol.

According to another of its aspects, the present invention relates tothe use of ursodeoxycholic acid or tauroursodeoxycholic acid for thepreparation of injectable formulations suitable for the treatment ofpathological conditions of the liver in patients for whom the oraladministration of drugs is impossible.

Said formulations are useful in subjects who have undergone a transplant(for example liver, heart, bone marrow, kidney) in order to combat thehepatotoxic effects of the drugs which are normally administeredfollowing the transplant intervention; in subjects suffering fromhepatic insufficiency; in subjects who are being fed entirely by theparenteral route; in subjects who have undergone a massive intestinalresection which requires an extended fast; and in newborns and childrensuffering from hepatic cholestasis.

The duration of the treatment involving the slow intravenous perfusionof ursodeoxycholic acid or tauroursodeoxycholic acid, administeredpreferably by means of the formulation forming the subject of theinvention, varies according to the pathological conditions to betreated. In general, said duration varies from 1 to 30 days,advantageously from 3 to 10 days and preferably from 5 to 7 days.Several treatment cycles can be carried out if necessary.

Of course, the daily dose of active principle to be administered variesaccording to the patient's age and weight and according to the type andseverity of the pathological condition to be treated.

In general, the daily dose of active principle to be administeredaccording to the present invention (expressed in mg of acid) is between2 and 30 mg/kg body weight, advantageously between 4 and 20 mg/kg andpreferably between 8 and 15 mg/kg. For an adult of normal constitution,the daily dose is between 500 and 2000 mg.

The unit doses can therefore contain from 100 to 2000 mg of activeprinciple (expressed in mg of acid). After appropriate dilution in thesolution for intravenous perfusion, said unit doses can be administered1 or more times a day, as required.

According to one preferred aspect, the unit doses contain 250 or 500 mgof active principle (expressed in mg of acid) in volumes of 2.5 and 5 mlrespectively.

The Example which follows illustrates the invention more clearly.

EXAMPLE 1

INJECTABLE COMPOSITION BASED ON 10% URSODEOXYCHOLIC ACID--Ampoulescontaining 250 mg of ursodeoxycholic acid

A solution of 20 g of sodium hydroxide in 200 ml of distilled water anda solution of 2 g of trometamol in 50 ml of distilled water are added toa suspension of 200 g of ursodeoxycholic acid in 1300 ml of distilledwater. If appropriate, a few drops of 1N aqueous sodium hydroxidesolution are added to the resulting mixture until it becomes clear. Itis diluted with distilled water qsp ad 2000 ml. It is filtered through aMillipore® HAWP 0.45 μ membrane+Millipore® AP25 prefilter. Under anitrogen atmosphere the solution obtained is divided up into 800ampoules of neutral white glass for injectable compositions, 2.5 ml ofsolution being poured into each ampoule. The ampoules are sterilized inan autoclave at 121° C. for 30 minutes.

The ampoules obtained in this way are suitable for dilution in anisotonic solution and administration by slow perfusion.

EXAMPLE 2

INJECTABLE COMPOSITION BASED ON 10% URSODEOXYCHOLIC ACID--Ampoulescontaining 500 mg of ursodeoxycholic acid

The title composition is obtained by following the procedure describedin Example 1 except that 5 ml of solution are poured into 400 ampoules.

We claim:
 1. An injectable aqueous composition which comprisesursodeoxycholic acid or tauroursodeoxycholic acid, a strong basecompatible with intravenous administration, and trometamol.
 2. Acomposition according to claim 1 wherein the active principle is presentin an amount of between 1 and 30% (w/v).
 3. A composition according toclaim 1 wherein the strong base is sodium or potassium hydroxide.
 4. Acomposition according to claim 3 wherein the strong base is present inan amount stoichiometrically equivalent to the active principle.
 5. Acomposition according to claim 1 wherein the trometamol is present at arate of 0.01-2% (w/v).
 6. A composition according to claim 1 whichcomprises from 5 to 15% (w/v) of ursodeoxycholic acid, astoichiometrically equivalent amount of a strong base selected fromsodium or potassium hydroxide and from 0.05 to 0.2% (w/v) of trometamol.7. A composition according to claim 6 which comprises about 10% (w/v) ofursodeoxycholic acid, about 1% (w/v) of sodium hydroxide and about 0.1%(w/v) of trometamol.
 8. A composition according to claim 7 wherein saidcomposition is subdivided into unit doses containing 250 or 500 mg ofursodeoxycholic acid.
 9. A method for the treatment of pathologicalconditions of the liver in patients for whom the oral administration ofdrugs is impossible or difficult which comprises administering to apatient in need of such treatment a composition according to claim 1.10. A method for the treatment of the hepatotoxic effects of the drugswhich are normally administered following the transplant intervention insubjects who have undergone a transplant which comprises administeringto a patient in need of such treatment a composition according toclaim
 1. 11. A method for the treatment of pathological conditions ofthe liver in subjects suffering from hepatic insufficiency; in subjectswho are being fed entirely by the parenteral route; in subjects who haveundergone a massive intestinal resection which requires an extendedfast; and in newborns and children suffering from hepatic cholestasiswhich comprises administering to a patient in need of such treatment acomposition according to claim
 1. 12. A composition according to claim 1wherein the active principle is present in an amount of between 5 and20% (w/v).
 13. A composition according to claim 1 wherein the activeprinciple is present in an amount of about 10% (w/v).
 14. A compositionaccording to claim 1 wherein the trometamol is present at a rate ofabout 0.1% (w/v).